[Frontiers in Bioscience 16, 759-769, January 1, 2011]

Chemoprevention of hepatocellular carcinoma by acyclic retinoid

Masahito Shimizu, Hiroyasu Sakai, Hisataka Moriwaki

Department of Medicine, Gifu University Graduate School of Medicine, Gifu, Japan 501-1194

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Retinoids and their receptors
4. Abnormalities in the retinoid/retinoid receptor axis and HCC
5. ACR in HCC chemoprevention: Experimental studies
6. ACR in HCC chemoprevention: Clinical studies
7. "Clonal deletion" therapy for HCC
8. "Combination chemoprevention" of HCC using ACR as the key drug
9. Perspective
10. Acknowledgements
11. References

1. ABSTRACT

The prognosis for patients with hepatocellular carcinoma (HCC) is poor and effective prevention strategies are urgently required. Here, we review abnormalities in the expression and function of retinoids and their receptors, and how they play a critical role in the development of HCC. In particular, a malfunction of RXRalpha due to phosphorylation by Ras-MAPK signaling pathway is profoundly associated with liver carcinogenesis and thus may be a promising target for HCC chemoprevention. Acyclic retinoid (ACR), a synthetic retinoid, inhibits Ras-MAPK activation and RXRalpha phosphorylation, thereby suppressing growth in HCC-derived cells. In clinical trials, ACR has been shown to improve patient survival by preventing viral HCC development, a possible manifestation of the concept of "clonal deletion" therapy. "Combination chemoprevention" with ACR as the key drug has great potential to become an effective strategy for the prevention of liver carcinogenesis. In summary, both basic and clinical research strongly suggest that ACR plays a critical role in preventing the development of HCC and that "clonal deletion" therapy is one of the most practical approaches for this purpose.